Study Questions:

What is the efficacy of macitentan, a new dual endothelin-receptor antagonist (ETa), in patients with pulmonary arterial hypertension (PAH) using endpoints of morbidity and mortality in a long-term trial?

Methods:

Patients with symptomatic PAH were randomly assigned to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for PAH other than ETa’s, was allowed at study entry. The primary endpoint was the time from the initiation of treatment to the first occurrence of a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH.

Results:

There was no difference between groups for mean age of 46 years, 77% female, 98% WHO class II-III, 55% idiopathic PAH, 31% associated with connective-tissue disease, and 8% congenital systemic-to-pulmonary shunts; 36% were previously untreated and 61% were on a phosphodiesterase-5 (PDE-5) inhibitor. Mean duration of the study for the two active treatment arms was 101 weeks. A total of 250 patients were randomly assigned to placebo, 250 to the 3 mg macitentan dose, and 242 to the 10 mg dose. The primary endpoint occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3 mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52-0.96; p = 0.01), and the hazard ratio for the 10 mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39-0.76; p < 0.001). Worsening of PAH was the most frequent primary endpoint event. The effect of macitentan on this endpoint was observed regardless of whether the patient was receiving therapy for PAH at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. There was no signal of hepatic toxicity.

Conclusions:

The authors concluded that macitentan significantly reduced combined morbidity and mortality among patients with PAH in this event-driven study.

Perspective:

Pulmonary hypertension specialists have encouraged event-driven trials in PAH rather than using surrogate endpoints including relative improvement in 6-minute walk distance (6MWD) and time to clinical worsening. In this study, the 6MWD increased very modestly (12.5 m at 6 months), yet the reduction in endpoints was detectable within 2 years and over 50% were on a PDE-5 inhibitor. One of the issues for which the study was underpowered is the relative value of macitentan in connective tissue disease, a subset whose prognosis is comparatively poor regardless of treatment.